After more than 2 decades of change in the epidemiology of oropharyngeal cancers, the choice of optimal treatment for patients with human papillomavirus (HPV)–positive disease remains elusive. Investigators are testing strategies that could reduce the intensity of treatment for patients who are HPV positive and lessen the often serious long-term adverse events (AEs) while maintaining efficacy.

Clinical trial results available thus far indicate that a subgroup of patients who are HPV positive and have good prognoses may be safely treated with a lower-than-standard radiation dose after chemotherapy. Other studies that are testing various combinations of surgery, chemotherapy, radiation, and immunotherapy, as well as strategies for identifying patients who are eligible for less intense treatment, are expected to report out over the next few years.

Although some clinicians have individually started to deintensify treatment of their patients who have HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), experts say the research has not yet established solid guidelines for practices generally. The question of how best to approach deintensification remains controversial, and investigators say more high-quality trials are necessary to make clear which new therapy sequences add benefit and in which patients.

“This is a work in progress, and I don’t think we’ll have an agreed-upon gold-standard deintensification method for another 10 years, maybe. But we’re heading in that direction,” said Nabil F. Saba, MD, director of the Head and Neck Medical Oncology Program of Winship Cancer Institute at Emory University in Atlanta, Georgia. I use the analogy of Hodgkin disease, where we started treating this with very intensive radiation decades ago, the deintensification took place, and then people moved away from high-dose radiation to chemotherapy. This process took a significant time and effort and it continues to evolve.”

Interest in deintensification crystallized nearly 10 years ago as HPV-related head and neck cancers became more common and were recognized as a clear clinical and pathologic subtype. Retrospective studies found a pattern of better outcomes for patients who tested positive for the p16 tumor suppressor protein, which is highly correlated with HPV infection.

Important trials examining this question include the analysis of the phase III Radiation Therapy Oncology Group (RTOG) 0129 trial, published in 2010, which found that patients with locally advanced head and neck cancer that is correlated with HPV had better 3-year rates of overall survival (OS) than patients who were HPV-negative (82.4% vs 57.1%, respectively). Those with HPV-positive disease had a 58% reduction in the risk of death after adjustment for tobacco exposure and other variables (HR, 0.42; 95% CI, 0.27%-0.66%).1

Deintensification had not previously been a focus because patients with OPSCC generally have poor prognoses, according to Saba. Patients with HPV-negative tumors who receive standard treatment have 5-year survival rates of about 50%, he said, and studies often find poorer outcomes for OPSCC subgroups. Research is focused on extending survival, in some cases by testing maximum tolerable dosing, rather than on mitigating the harms resulting from treatment.

However, those long-term effects can substantially affect survivors’ quality of life. That is of particular concern for the growing number of patients who are treated successfully at a relatively young age, many of them nonsmokers with HPV-positive disease, and who experience life-long toxic effects. For example, dysphagia, or swallowing dysfunction, is “a debilitating, depressing, and potentially life-threatening complication” that persists long after treatment is complete.2 The probability of dysphagia increases 19% with every additional 10 Gy of radiation.3

Other late chemoradiation effects can include xerostomia (dry mouth), aspiration of foreign objects, feeding tube dependence, hyperthyroidism, neck fibrosis, and osteonecrosis. “We’re dealing with the patients who are 10 years out from chemoradiation and they’re miserable. And it’s not fixable,” said Robert L. Ferris, MD, PhD, director of the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.

Rates of HPV-positive oropharyngeal cancers in the United States more than doubled from 1988 to 2004 while the incidence of HPV-negative cancers fell by half.4 The virus is now thought to cause 70% of oropharyngeal cancers in the United States.5